Adipokines: A gear shift in puberty

Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic‐pituitary‐gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in childhood obesity and puberty onset variability.


| INTRODUCTION
The prevalence of obesity in adolescents and children is increasing in alarming rates. 1,2 Specifically, worldwide, 41 million children below the age of 5 years were overweight or were with obesity in 2016, and this number is expected to increase to 70 million in 2025. 3 Childhood obesity is associated with various severe health complications, including increased risk of diabetes mellitus type 2, hypertension, heart diseases, and disturbances in sex hormone levels.
Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) above 30. 4 Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and function. 5,6 BAT consists of adipocytes containing multiple lipid droplets and mitochondria and plays a role in thermogenesis. Adipocytes in WAT contain only a few mitochondria and a single lipid droplet. [5][6][7] Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines (hormones, cytokines, and peptides). 5,7,8 Adipokines are involved in a number of physiological processes including blood pressure, metabolism, glucose, and vascular homeostasis and may play amongst others a key role in puberty onset. [8][9][10] Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproductive functions. 9,11 Although many studies have shown associations between obesity and puberty, 2,12-23 the biological mechanisms underlying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity.
androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal growth spurt, body odor, skin oiliness, and skeletal maturation. 9,24,25 Both adrenarche and gonadarche are involved in the development of pubic hair. 25 During gonadarche (Figure 1), the hypothalamicpituitary-gonadal (HPG) axis is activated, 2,26 and several hormones have been identified to participate in the activation of the HPG axis including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized neurons, the KNDy neurons in the hypothalamus. 28 Kisspeptin is a key regulator of the pulsatile secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. 29,30 In addition, neurokinin B stimulates, and dynorphin inhibits the release of kisspeptin, which implies that both coordinate a pulsatile release of kisspeptin. 31 Subsequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular volume in boys. 2,26,32 The age at puberty onset varies greatly among individuals, which is possibly due to differences in levels of body fat, hypothalamic-pituitary-adrenal (HPA) axis activity, and genetic background. 33 Recent genome-wide association studies have provided important new insights on new genetic loci (e.g. melanocortin-4 receptor, mitochondrial carrier 2, and mitogen-activated protein kinase 13) and on several pathways that regulate the timing of puberty; however, it partly explains puberty timing variation. 34 Thereby, defining the role of adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sexual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche.
Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next sections. 2,24

| THE ONSET OF PUBERTY IN GIRLS
Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of menstruation), 19 and pubic hair development. 35 The average age of girls at start of menarche is 12.4 years. 36 However, this age differs between cultures and ethnicities, and since 1980, age at menarche is significantly decreasing. [36][37][38][39] F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively

| Fat storage
For the initiation of puberty, the timing of stimulation and/or inhibition of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menarche, which emphasizes the importance of body fat. From an evolutionary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy pregnancy, offspring, and maternal survival. 40 An improper level of body fat, sex-hormones, and neuroendocrine alterations can evolve in menstrual dysfunction, for instance, in women with severe obesity or in women with anorexia nervosa. [41][42][43] Importantly, body fat distribution, particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than amount of total body fat. [44][45][46] Blood leptin levels are strongly related to gluteofemoral fat depots suggesting that leptin may convey information on body fat distribution to the hypothalamus during puberty. 45

| HPG axis
The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the

| Adipokines
According to results from studies reported in Table 1 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both the HPA and HPG axes. 33 These axes are functionally integrated during adrenarche. In coherence, in children with obesity, the androgen DHEAS was positively associated with leptin levels. 55 Nevertheless, another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI levels. 55 In addition, the adipokine adiponectin was negatively associated with androgen levels in girls 56 ; however, it was not related to adrenarche in girls with Prader-Willi syndrome. 57 Interestingly, sex differences of adiponectin seem to develop during the progression of puberty. 56 Thus, leptin and adiponectin might be able to influence adrenarche; however, both are not required factors.  63 These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin concentrations in girls. 63 In addition, individuals with obesity often develop a chronic low-grade inflammatory state, which can be indicated by a high level of circulating inflammatory cytokines like TNF-α and IL-6. 64 TNF-α alters, and IL-6 inhibits the expression of adiponectin ( Figure 2). 8 Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obesity can promote the onset of puberty.
Thus, specifically leptin, adiponectin, and inflammatory cytokines produced by WAT could be permissive key players during an early onset of puberty in girls with obesity. 9,36,62,68 As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral reproductive function as HMW is not able to cross the blood brain barrier. 63

| THE ONSET OF PUBERTY IN BOYS
Markers that are used to assess puberty onset in boys are spermarche, voice break, testicular volume, and pubic hair development. 35 While pubic hair development, larger testicular volume, and spermarche develop in the early stages of puberty onset, voice break usually appears in later stages of puberty. 69 Generally, first testicular volume increases, which occurs at an average age of NIEUWENHUIS ET AL.

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F I G U R E 2 Adipokines affecting the initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNFα and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an average age of 13.4 years. 70

| Fat storage
Many aspects of the reproductive physiology are energetically demanding, 71 and therefore, an adequate energy level is necessary.
In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of fat. 72 Subsequently, a growth spurt follows in which they gain tissue mostly consisting of lean mass, which causes exhaustion of most of their body fat. 72 These alterations in amount of body fat indicate that in boys, an adequate amount of body fat is important in the onset of puberty. 73

| HPG axis
Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH from the pituitary gland ( Figure 1). 9,74 FSH induces spermatogenesis, and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and subsequently GnRH from the hypothalamus. 9,48 Contrarily to women, in men, the release of kisspeptin is more consistent, causing a constant release of LH. 29,48 LH-induced testosterone levels lead to the development of secondary sex characteristics in boys. 9 In more detail, differences between sexes in kisspeptin release are related to a sexspecific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid receptors expressed on KNDy neurons. 48 In humans, KNDy neurons in the infundibular nucleus are involved in negative and positive sexsteroid feedbacks. 48 These sexual dimorphisms are induced by perinatal exposure to sex steroids and result in sex-specific differences in kisspeptin release. 75,76

| Adipokines
The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased BMI, 14,17,22,23,50,51,77,78 while others reported no associations at all 20,49 or a delayed onset of puberty 79 (Table 1). 16,80 The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes, 33 and moreover, androgen levels were positively associated with plasma leptin levels. 55 Nevertheless, enhanced adrenal androgen secretion in boys with premature adrenarche was not related with leptin levels. 55 Thereby, leptin plausibly has a minor impact in adrenarche in boys.
Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obesity. 61,62 Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit adiponectin, and individuals with obesity often have high levels of circulating inflammatory cytokines. 64 High leptin and low adiponectin levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of testosterone from the testes, 58 and fat tissue can convert testosterone to estrogen ( Figure 3). 2,60-62 Both processes might result in the delay of the development of secondary sex characteristics in boys. 29,61,79 Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and expression of the leptin receptor in the testis. 81,82 In men, other adipokines like chemerin are found in the gonads too. 65 Thereby, resistin is expressed in the testes of rats, but its exact function and role still have to be examined. 83 Figure 4). [12][13][14][15]17,[20][21][22][23]49,[77][78][79]84,85 In addition, the inclusion of a proper age range (8-16 years) is important when assessing the onset of puberty. 30,47 Furthermore, comparison between studies from different time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or overweight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies use the same anthropometric standards and sex-specific cut-offs. 86 Specifically in children, BMI is often dependent on age and growth spurts. 13,14,[16][17][18][19][20][21][22][23][49][50][51][77][78][79][80]   Selection criteria used were English language, longitudinal or cross-sectional studies assessing the onset of puberty, including menarche, thelarche, spermarche, or voice break, combined with high BMI or obesity/adiposity, and articles assessing or reviewing adipokines and its effects on the reproductive system.

CONFLICTS OF INTEREST
The authors declare no conflict of interest.